The objectives of this proposal are to understand the role of the central cholinergic system in (1) the analeptic action and (2) the sensitization phenomenon associated with cocaine and amphetamine. Both of these stimulants, when administered to pentobarbital-anesthetized rabbits, shorten the duration of narcosis. This arousal (analeptic) response, and the appearance of hippocampal theta in the EEG, are blocked by atropine or scopolamine. In this proposal we plan to characterize further the cocaine and amphetamine-induced analeptic effect, then to localize by microinjection techniques the brain site(s) at which these drugs initiate the analeptic response. Upon finding the site(s) we will conduct lesioning experiments to determine the brain pathways that are involved in the response. Drug interaction studies with specific neurotransmitter antagonists and depletors that are known to affect aspects of cocaine and amphetamine effects, will also be carried out to determine if other neurotransmitters might be involved in the cholinergically mediated analeptic effect. These studies should clarify the role of central cholinergic mechanisms in the analeptic effect of cocaine and amphetamine. In recent preliminary experiments we discovered that atropine attenuated the development of locomotor sensitization when it was administered daily with cocaine to rats. Also, high affinity choline uptake (HACU) was increased in cortex and hippocampus of rats given repeated intermittent doses of cocaine. These two sets of data, while preliminary, suggest that central cholinergic mechanisms might be associated with the sensitization process. The present proposal will attempt to clarify that association. Rats will be administered cocaine chronically with and without anticholinergies or their quaternary analogs. In other studies medial septal lesions to block hippocampal cholinergic activity will be examined for their influence on development of supersensitivity. Changes in HACU activity and 3H-QNB binding in several brain regions will be monitored during chronic cocaine treatment of rats. These studies will provide new information of the role of central cholinergic mechanisms in cocaine and amphetamine sensitization.